AU598454B2 - Compositions and methods for retarding the effects of aging of the skin - Google Patents

Description

)4 5854 FORM 10 SPRUSON FERGUSON COMMONWEALTH OF AUSTRALIA PATENTS ACT.1952 COMPLETE SPECIFICATION (OR IGINAL) FOR OFFICE UJSE: This dO tUrf~mad ue a~drn~~tSd V Orrect fOf sectionl 9 at Class Int. Class grin il g.

Complete Specification Lodged: Accepted: Publisbed: Priority: dO~ YT~B~NI Related Art: 3 Name of Applicant: ALBERT M. KLIGMANsdeV Address of Applicant: 637 Pine Street, Philadelphia, PA 19106, United States of America Actual Inventor: ALBERT M. KLIGMAN C ,Address for Service: Spruson Ferguson, Patent Attorneys, Level 33 St Martins Tower, 31 Market Street, Sydney, New South Wales, 2000, Australia Complete Specification for the invention erititled: "COMPOSITIONS AND METHODS FqR RETARDING THE EFFECTS OF AGING OF THE SKIN" The following statement is a ful ,2escripti6,i of this inventiocn, iRncluding the best, method, of performing it kVown to me SBR: ALB: 8i IV.U i[ i:' i: t n L. i ii I. i :i i I- _I W P I *094 4 t *4 4, 1'1 *r 4' 44C *i Abstract of the Disclosure Various effects of photo-aging (sundamage) of the skin including impairment of the differentiation of epidermal epithelial cells, loss of collegan fibers, abnormal changes in the elastic fibers, and deterioration of small blood vessels in the dermis of the skin are retarded by applying topically to the epidermis of the skin in a proqram of maintenance therapy effective amounts of vitamin A acid (tretinoin) such that epithelial growths are substantially reduced and prevented, and the skin substantially regains and maintains its firmness, turgor and elasticity, Moreover, with persistent treatment dermal blood cells and vessels increase and thd epidermis and dermis thicken, resulting in improved ability of the skin to sense, resist and recover from irritation or injury. Further, hyperpigmentation, lines and wrinkles due to aging are reduced and prevented. The treatment is particularly useful for human facial skin and preferably applied in an emollient vehicle in sub-irritating doses.

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i la Field of the Invention This invention relates to methods of 1 5 using vitamin A acid to retard the effects of aging 00n0 S: of the skin and generally improve the quality of o the skin, particularly photo-aging of human facial 0 skin, "Background of the Invention Caucasians who have had a good deal of sun exposure in childhood will show the following S gross cutaneous alterations in adult life: I 00 wrinkling, leatheriness, yellowing, looseness, roughness, dryness, mottling (hyperpigmentation) 15 and various premalignant growths (often 0 00* 0. subclinical). These changes are most prominent in light-skinned persons who burn easily and tan poorly. The baleful effects of sunlight are Scumulative, increasing with time. Although the anatomic degradation of the skin is most advanced 2 in the elderly, the destructive effects of excessive sun exposure are already evident by the second decade. Serious microscopic alterations of the epidermis and dermis occur decades before these become clinically visible. Wrinkling, yellowing, leatheriness, loss of elasticity are very late EC changes.

It is known to use vitamin A acid for the S"C treatment of acne as set forth in my U.S. Patent t t 10 No. 3,729,568. Other known uses of vitamin A acid which were reviewed by Thomas and Doyle in Journal of American Academy of Dermatology (May, 1981) Vo- 4 lume No. 5, include, in addition to acne treatment, treatment of senile comedones, nevus comedonicus, linear verrucous nevus, plantar warts, pseudofolliculitis, keratoacanthoma, solar keratosis of extremities, callosities, keratosis t palmaris et plantaris, Darier's disease, ichthyosis, psoriasis, acanthosis nigricans, lichen planus, molluscum contagiosum, reactive perforating collagenosis, melasma, corneal epithelial peeling, i geographic tongue, Fox-Fordyce disease, cutaneous metastatic melanoma and Keibois or- hypertrophic I- 1 3 scars. Vitamin A acid derivatives (retinoids) are known to have prophylactic and therapeutic effects on a great variety of tumors and are being increasingly used as anti-tumor drugs.

In view of the foregoing, it is believed that vitamin A acid influences ultrastructural and proliferative properties of epidermal cells.

However, these prior art uses of vitamin A acid have generally involved short term treatments in i "i 10 which relatively large doses of the acid are applied sufficient to cause significant Sirritation and often peeling) in order to obtain a quick cure or treatment of the particular condition, such as removal of comedones, as opposed to persistent treatment of normal aging skin.

Brief Summary of the Invention The present invention relates to the use of low strength vitamin A acid (retinoic acid), known clinically as tretinoin, in moderating and preventing the aging changes of the exposed areas of the skin, especially the face. In particular, the methods of the present invention retard the 4,II, effeci:s of photo-aging of the skin Including Impairment of the differentiation of epidermal epithelial cells, loss of collagen fibers, abnormal changes In the elastic fibers, and deterioration of small blood vessels of the dermis of the skin.

Thus In a first embodiment of the Invention there is provided a method for retarding and reversing the loss of collagen fibers, abnormal changes in elastic fibers, the deterioration of small blood vessels of the dermis of the skin, and the formation of abnormal epithelial growths in sundamaged human skin, comprising applying topically to the epidermis of the skin a composition comprising effective amounts of vitamin A acid in a non-toxic, dermatologically acceptable vehicle in a program of maintenance therapy, whereby the skin substantially regains and maintains its firmness, turgor and elasticity during said therapy, said composition and amounts of vitamin A acid being selected so as to provide a dose of vitamin A acid which Is Insufficient to cause excessive irritation to the skin.

Generally, the maintenance therapy is begun in middle age when :epithelial growths and other aging changes begin to appear clinically.

In a second embodiment of the Invention there is provided a composition for topical application to the epidermis of the skin for use in ,t*ZO retarding and reversing the loss of collagen fibers, abnormal changes in elastic fibers, the deterioration of small blood vessels of the dermis, and the formation of the abnormal epithelial growths in sundamaged human skin, comprising effective amounts of vitamin A acid In a non-toxic dermatologically acceptable vehicle, said composition and amounts of vitamin A acid being selected so as to provide a dose of vitamin A acid i which Is insufficient to cause excessive irritation to the skin.

The vitamin A acid may be applied to the skin In any suitable non-toxic, dermatologically acceptable vehicle, preferably a non-volatile, emollient or lubricating vehicle, In an amount and at a frequency which are Insufficient to cause excessive Irritation of the skin. Generally, concentrations in the range of about 0.005 to 0.05% by weight of the vehicle are preferred.

TMS/892c r'1 Detailed Description of the Preferred Embodiments 4210 ct c ic 14 cl 4 4r 41 Cr The purpose of this invention is to moderate and retard the photo-aging changes in the skin by topical application of tretinoin beginning in middle age when such changes first become evident clinically. Certain of the anatomic alterations can be corrected and at least partialy reversed, accompanied by improvement in the appearance of the skin.

The invention accomplishes two goals.

First, a prophylactic effect in preventing progression and worsening of the damage with the passage of time. Secondly, various abnormalities are corrected and modified to the extent that the structure and function of the skin acquires the characteristics of younger skin.

Age Associated Structural Changes Although many of the effects of the aging of the human skin are the result of underlying structural changes which build up over a period of years and can only be detected histologically it r.-e j

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c r C Cr Cg 1'0 Ci I C C prior to middle age, these changes and effects begin to appear clinically about middle age, namely between about 35 and 45 years of age, and become more and more evident and pronounced thereafter.

The more apparent effects of aging have already been referred to above, and each is associated with one or more underlying structural changes in the skin. For example, blotchiness or mottling (hyperpigmentation) is due to changes in the melanocytes in the population of epidermal cells.

These pigment producing cells, which unlike the keratinocytes remain at the base of the epidermis, lose their normal regulation process with aging and produce excess pigment which causes the botchiness and mottling.

However, aside from such obvious cosmetic changes in the skin, there are a number of other changes which are more important though less apparent, including loss of sensory acuity and ability to heal wounds, decreased blood flow and decrease in the thickness of the skin. Older people have less sensitivity to pain and a longer t 4 uc~r 4 44 wo* q 4 04 4 \l 10 *4 44 4 4 4 4 4 response time. Thus, pain due to irritation or injury is not felt as soon or to the same extent as in young people with the result that superficially minor but potentially serious injuries may be sustained without the individual being aware of the injury until serious damage has occured.

The surface temperature of the skin in older people is somewhat lower than the skin temperature in younger people, so that they often feel cold. This is diue to a decrease in the blood supply to the skin due to loss of small blood vessels'and decreased proliferation of new capillaries and small blood vessels in the skin.

This is at least one of the causes of the loss of sensory acuity and response to pain. Furthermore, the decreased blood supply decreases the rate at which irritants and toxins are cleared from the skin tissue.

Still further, the skin of older people is more easily torn than that of younger people, since both the epidermis and dermis become thinner with age. As a result, there is less bulk to protect underlying organs and therefore more risk 8 of serious injury. Moreover, when wounds or injuries are sustained, healing of the wounds is much slower in older people and may take as much as twice as long to heal as in younger persons.

The underlying causes of the above gross skin effects may be understood more readily from the following discussion of the specific changes in the epidermis and dermis as aging progresses.

1. Epidermis With increasing exposure of a human to sun (photo-aging) and other environmental traumas, cells divide at a slower rate (decreased capacity to renew themselves). They show marked irregularities in size, shape and staining properties;, orderliness (polarity) from below to above is lost. The thickness of the epidermis decreases (atrophy). The horny layer which comprises the barrier against water loss and penetration of chemicals becomes abnormal due to the shedding 20 (exfoliation) of cells in large groups or clusters instead of as individual cells, resulting in roughness, scaling and dryness. There is loss of 7-' 1 1 9 the orderly transformation of living epithelial cells into cornified dead cells which are shed at the surface, that is, differentiation is impaired.

Aberrant differentiation results in numerous foci of abnormal epithelial growths or tumors, the most frequent and important of which are actinic keratoses. After many years these can transform into frank skin cancers called basal cell and squamous cell cancers. Pigment producing cells (melanocytes) can also become altered forming flat, dark growths (lentigo melanoma) which may progress to malignant melanoma. The cells which make up these premalignant growths are destroyed by topical tretinoin.

2.Dermis The cells which make the fibers of the dermis become smaller and sparser with increasing age, usually in sundamaged facial skin. There is a great loss of collagen fibers resulting in looseness and easy stretchability of the skin; elastic fibers become abnormal so that the skin does not promptly snap back after being stretched.

Since the fibrous components comprise more than of the bulk of skin of which 95% is col.agen, the degradation of these fibers, especially collagen, is mainly responsible for wrinkling, laxness and loss of elasticity.

Small blood vessels become thin walled, delated and often ruptured. Vascular supply thereby becomes compromised.

Beneficial Effects of Tretinoin in Accordance With the fPesent Invention Increases proliferative activity of epidermal cells. This results in thickening of the epidermis with correction of atrophy. Cell renewal c *e is quickened so that cells divide at a rate typical of younger skin. Treatment with vitamin A acid in accordance with the invention can double the skin thickness. The stimulation of cell growth also results in faster wound healing. Experiments have been performed wherein blisters have been raised and cut off on skins of individuals of various Sages. Healing takes place in 2 or 3 weeks in young people, but takes much longer in older persons with sun damaged skin.

r: hi?. r I-a 11 Application of tretinoin before raising the blister results in healing twice as fast in the older subjects.

Corrects abnormalities of differeatiation. Vitamin A acid regulates and controls the physiologic behavior of epithelial tissue, assuring its stability and integrity. It corrects and normalizes abnormalities of differentiatio. In sundamaged skin, the numerous foci of abnormal growths and segments of atypical, abnormal epidermis are corrected, reversed or eliminated. Fewer growths appear and progression to cancer is halted. Normalizing of the epidermis.

results in a smoother, less dry and rough skin, since cells are not only produced more rapidly but elxfoliation occurs by individual cells rather than clusters or scales, thus improving the topography of the skin. Moreover, hyperpigmentation resulting in blotchas and splotches is reduced by tretinoin stopping excessive production of pigment by the melanocytes, although it cannot eliminate depigsantation.

i °.ix l 1 f 1 12 The metabolism of fibroblasts is increased. Fibroblasts synthesize the fibers of the dermis; new collagen is laid down, strengthening the physical foundation of the skin.

Fibroblasts also make the ground substance which exists between the fibers, allowing these to glide past each other. The ground substance, known as acid mucopolysaccharides, is also responsible for the turgor and bounce of the skin. Tretinoin stimulates the formation of new acid mucopolysaccharides.

Accordingly vitamin A acid promotes the formation of a more normal dermis. Because of this activity, it has been found to promote and accelerate the healing of wounds in compromised tissue, of which regressed, aged dermis is an example. Further, the production of a new collagen layer not only repairs damaged skin but results in the effacement and prevention of fine wrinkles and lines.

Vascularity is increased. Tretinoin stimulates blood flow and promotes the formation of new vessels. Blood flow is greatly reduced in 13 aged, sundamaged skin. A brisker blood supply improves the physiologic competence of the skin and imparts a livelier, glowing appearance. Patients often say their skin feels "more alive".

Several of the prior art treatments of skin disease using vitamin A acid as referred to above have claimed there is an increase in the blood flow in the skin. However, the increased blood flow from such short term treatments results simply from vasodilation caused by the irritating effects of high concentrations of vitamin A acid.

In contrast, the low sub-irritating concentrations of vitamin A acid according to the present invent tion do not cause significant vasodilation, but it has been found that over the long term there is not only a proliferation of new blood vessels, but also an increase in lymphocytes and other blood cells.

As a result, there are more cells to fight infection, and the increased blood supply allows the skin to clear irritants and toxins more quickly E fom the skin.

Still further, treatment with vitamin A p n 1 I^e 14 acid according to the present invention raises the surface temperature of the skin by about 1/2 degree centigrade due to the greater basodermal flow of blood. The increased blood flow also increases acuity to pain and irritation, and the skin becomes more reactive to chemical insults. For example, experiments with highly drying and irritating cosmetics, soaps, perfumes, etc. have shown that young people will experience severe irritation within 3 or 4 days whereas it may take 2 to 3 weeks Sfor ai older person to feel the same irritation.

The irncreased sensitivity of the skin treated with vitamin A acid provides an early warning system to older people so that too much damage is not done before the pain or irritation is fe7t.

Tretinoin may be formulated in bland, moisturizing bases, such as creams or ointments, in the broad concentration range of about 0.0001% to CC 0.05%, usually about 0.005% to 0.025% and preferably about 0.01% by weight of base, although higher concentrations may be used for darker skins.

Other non-toxic, dermatologically acceptable vehicles or carriers in which tretinoin'is stable will be evident to those of ordinary skill in the art. In general, emollient or lubricating vehicles, such as oleaginous substances, which help hydrate the skin are preferred. Volatile vehicles which dry or otherwise harm the skin, such as alcohol and acetone, should be avoided.

An ointment base (without water) is preferred in the winter and in subjects with very dry skin. Examples of suitable ointment bases are petrolatum, petrolatum plus vol-tiile silicones, and lanolin.

In warm weather and often for younger persons, emulsion (cream) bases, which are mixtures of oils and water are preferred. Examples of suitable cream bases are Eucerin (Beiersdorf), cold cream (USP), Purpose Cream (Johnson Johnson), and hydrophilic ointment (USP).

Tretinoin is a mild irritant and may Scause redness and scaling, which may be accompanied by some tenderness and tightness. These reactions quickly disappear when the applications are stopped. However, even when applied excessively to \7:1' 16 produce an intense dermatitis, the reaction fades quickly leaving no permanent sequellae. Systemic side reactions are unknown. Selection of an appropriate emollient vehicle will more readily allow the use of a highly effective but subirritating dose of the vitamin A acid.

The extent or length of reatment according to the present invention may best be described as persistant or indefinite. That is, compared to the short term prior art treatments of various conditions with vitamin A acid in which the treatments are terminated as soon as the condition disappears or subsides, the treatment according to the present invention is intended to continue indefinitely, otherwise the effects of aging will reappear after treatment is terminated. That is, the treatments of the present invention may be considered to be intervention therapy in decelerating the photo-aging process. If the intervention is stopped, there is regression to the j original state.

Usually, there is lit'tle point in ibeginning the treatments of the present invention 17 until middle age when the effects of photo-aging 'bgin to appear clinically. The particular program of maintenance therapy according to the present invention will vary depending upon the individual being treated. Generally, depending upon the age and state of the skin when treatments begin, it has been found that once a day applications of vitamin A acid for up to 6 months may be necessary to reduce and control the effects of aging which have already occurred. Once a stabilized skin control has been obtained, the frequency of application of vitamin A acid may be reduced, for example to two or three times a week, and in some cases only once.

a week for the rest of the person's life. That is, once the aging process has been controlled, a maintenance dose on the order of two applications per week is generally sufficient to maintain that S state.

I i SThe invention will be illustrated in more 20 detail by reference to the following specific, nonlimiting examples: cr t t 15 1 t Experimental Example 1 There has been applied 0.01% to 0.025% by weight concentrations of tretinoin in a base to the faces of middle-aged and elderly women. At least 500 persons have used typical tretinoin experimentally for periods ranging from three months to five years. These women were studied as follows: About two hundred were inmates of the Philadelphia Home for the Indigent at Riverview.

They ranged in age from 45 to 75. The creams or ointments containing Vitamin A acid (tretinoin) were applied once daily before bedtime in an amount sufficient to achieve a continuous sustaining film., Clinical assessments were made once monthly. Beneficial effects were obtained in about 80% after about three months. Most of those who improved continued to use tretinoin daily for one to two years. Improvement was maximal at about six months and persisted as long as the tretinoin was used.

Withdrawal of tretinoin resulted in a slow loss of improvement with a return to the original state in about four to five months. Maintenance therapy was ira *r t

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2' ic j 19 required to prevent relapse.

The beneficial effects included effacement of small wrinkles, smoother surface, greater turgor, elimination of actinic keratoses, elimination of senile comedones, less conspicuous pores and less mottling (fading of pigmented spots).

Experimental Example 2 Histologic studies were conducted on twenty six residents of Riverview as follows.

Tretinoin was applied to one side of the face once daily as in Experimental Example 1 for four to six months. The other side received the cream or ointment base alone.

Biopsies were taken from both sides at the end of the study and processed for histologic examination using a variety of histochemical stains. The tretinoin treated side was easily

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c recognized in 24 of 26 subjects. The chief effects of tretinoin, as demonstrated by the indicated tissue staining techniques, were: a) Routine H E stain: epidermis thicker, polarity restored, cells were regular size and shape, loss of atypia, no epidermal irregularities or pre-malignant growths, density of fibroblasts increased, more vessels.

b) Fontanas stain for melanin: dispersion of pigment granules and far less pigment in epidermal cells.

c) Reticulin stain: increase in young collagen fibers indicating deposition of new collagen.

d) Orcein stain for elastin: moderate removalof degenerated elastic tissue, allowing intact fibers to be visualized more clearly.

Se) Hale's stain for ground substance: 15 definite increase in acid mucopolysaccharides, especially in deeper dermis.

Experimental Example 3 There have been treated at least another two hundred subjects in the. aging skin clinic at the Hospital of the University of Pennsylvania.

These are middle-class white women, ages 35 to Tretinoin was applied as in Experimental Example 1 for at least six months.

21 Beneficial effects were clinically evident in about 80% of these persons. With this more sophisticated group we took note of subjective reactions as well. These women uniformly thought that their skin was livelier, smoother, fresher, and tighter. Again, we noted more turgor, effacement of fine lines, less hyperpigmentation, more youthful appearance, less roughness, less wrinkling.

Experimental Example 4 About one hundred paid volunteers recruited at Ivy Research Laboratories have been studied in a variety of ways including biopsies, physiologic tests, etc. The importance of this series is that the tests were conducted according to the double-blind format and hence were strictly controlled. Tretinoin was applied once daily as in iyo' Experimental Example 1 for six to twelve months to one side of the face; the other side received the unmedicated vehicle. The applications were mada five days a week by a trained monitor who did not know which of the two preparations contained the 22 active agent. The clinical observations were made without knowledge of the drug treated side.

When the code was broken, some improvement was noted in about 15% of cases treated with the vehicle alone. Distinctly beneficial effects were secured in about 85% on the tretinoin treated side. Histologic study in thirteen cases confirmed the clinical results of restoration to a more normal pattern on the tretinoin side. The epidermal and dermal changes were those described above.

Fluorescein injected into both sides was removed in about half the time on the tretinoin side. This indicates improved vascularity resulting in faster clearance of drugs from the o skin. Moreover, a series of clinical stimuli indicate that tretinoin treated skin is more reactive, showing behaviors more typical of young I skin. It responds more rapidly and intensely to irritant chemicals such as creton oil and a dimethylsulfoxide; it blushes more readily after application of nicotinate; blisters raised by ammonium hydroxide heal more quickly (greater wound i i i i-- 4 4 1 15 f f 23 healing, a known effect of tretinoin); and contact allergic reactions (poison ivy) also heal more quickly.

From the foregoing, it will be seen that the invention has the following advantages inter alia: A. Clinical Effacement of fine wrinkles Smoother surface Lightens pigmented blotches Skin has more turgor Large pores less noticeable Skin feels livelier B. Histologic Thicker epidermis Normalizes atypia and pre-malignant changes..

Atrophy and dysplasia corrected.

Stimulates blood flow; new vessels formed.

Stimulates fibroblasts with new collagen formation.

Increases ground substance

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24 Melanin within keratinocytes is decreased.

It will be recognized by those skilled in the art that changes may be made to the abovedescribed embodiments of the invention without departing from the broad inventive concepts thereof. It is understood, therefore, that this o*O. invention is not limited to the particular embodiments disclosed, but it is intended to cover 10 all modifications which are within the scope and tt spirit of the invention, as defined by the appended claims.

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Claims (9)

1. A method for retarding and reversing the loss of collagen fibers, abnormal changes in elastic fibers, the deterioration of small blood vessels of the dermis of the skin, and the formation of abnormal epithelial growths in sundamaged huiian skin, comprising applying topically to the epidermis of the skin a composition comprising effective amounts of vitamin A acid in a non-toxic, dermatologically acceptable vehicle in a program of maintenance therapy, whereby the skin substantially regains and maintains its firmness, turgor and elasticity during said therapy, said composition and amounts of vitamin A acid being selected so as to provide a dose of vitamin A acid which is insufficient to cause excessive irritation to the skin.

2. The method according to claim 1 wherein said skin is human facial skin.

3. The method according to claim 1 or 2 wherein said therapy commences in middle aga of the subject to whose skin the vitamin A acid is applied. 4* 444, 44<4O i

4. The method according to any oie of claims 1 to 3 wherein said vehicle is an emollient vehicle.

The method according to any one of claims 1 to 4 wherein the concentration of vitamin A acid In said vehicle is 0.0001 to 0.025 weight percent of the vehicle.

6. A composition for topical application to the epidermis of the skin when used for retarding and reversing the 'loss of collagen fibers, abnormal changes in elastic fibers, the deterioration of small blood vessels of the dermis of the skin, and the formation of the abnormal epithelial growths in sundamaged human skin, comprising effective amounts S of vitamin A acid in a non-toxic dermatologically acceptable vehicle, said composition and amounts of vitamin A acid being selected so as to provide a dose of vitamin A acid which is insufficient to cause excessive irritation to the \kin.

7. The composition according to claim 6 wherein said vehicle is an emollient vehicle.

8. Composition according to claim 6 or 7 wherein the concentration of vitamin A acid in said Vehicle is 0.0001 to 0.025 weight percent of the vehicle. Vr^" 1 TMS/892c I 1. -26

9. A composition for topical application to the epidermis of the skin when used for retarding and reversing the loss of collagen fibers, abnormal changes in elastic fibers, the deterioration of small blood vessels of the dermis of the skin, and the formation of the abnormal epithelial growths in sundamaged human skin, substantially as hereinbefore described with reference to any one of the Examples. A method for retarding and reversing the loss of collagen fibers, abnormal changes in elastic fibers, the deterioration of small blood vessels of the dermis of the skin, and the formation of abnormal epithelial growths in sundamaged human skin, substantially as hereinbefore described with reference to Example 1. DATED this SIXTH day of APRIL 1990 Albert M, Kligman Patent Attorneys for the Applicant SPRUSON FERGUSON 1 TMS/892c